(E)-hept-2-enoic acid

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared as above from 165.4 mg (0.44 mmol) of the pyridyl ketone and 395.6 mg (0.87 mmol) of the Wittig salt. Preparative HPLC with MeOH-AcOH-CH2Cl2 (2:1:97) furnished 94.8 mg (46%) of the pure (E)-heptenoic acid: mp 67-72° C.; 1H NMR (CDCl3) δ8.60 (s, 1H), 8.48 (br s, 1H), 8.25 (s, 1H), 8.05 (d, J=8.2 Hz, 2H), 7.62 (distorted t, J=~5.3 Hz, 1H), 7.43 (br d, J=7.8 Hz, 1H), 7.28 (buried, 1H), 7.26 (d, 2H), 6.22 (t, J=7.4 Hz, 1H), 3.50 (m, 6H), 2.30 (ddd, J=7.1, 7.1, 6.9 Hz, 2H), 2.20 (ddd, J=7.6, 7.2, 6.9 Hz, 2H), 1.90 (tt, J=6.1, 6.1 Hz, 2H), 1.64-1.54 (m, 4H), 1.28 (t, J=7.0 Hz, 3H); FDMS 478 (M+1). Anal. (C27H31N3O5.0.6CH4O.0.8H2O) C, H, N.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared as above from 375.3 mg (0.88 mmol) of the pyridyl ketone and 796.8 mg (1.76 mmol) of the Wittig salt. Preparative HPLC with MeOH-AcOH-CH2Cl2 (4:1:95) yielded 266.2 mg (58%) of the pure (E)-heptenoic acid as a white fluffy sold: mp 48-55° C.; 1H NMR (CDCl3) δ8.60 (br s, 1H), 8.48 (br s, 1H), 8.26 (s, 1H), 8.06 (d, J=8.2 Hz, 2H), 7.48 (br s, 1H), 7.46 (br s, 1H), 7.38-7.25 (m, 6H), 7.27 (d, J=8.2 Hz, 2H), 6.20 (t, J=7.4 Hz, 1H), 4.57 (s, 2H), 3.67 (s, 4H), 2.32 (dd, J=7.1, 6.8 Hz, 2H), 2.20 (ddd, J=7.3, 7.2, 6.8 Hz, 2H), 1.68-1.52 (m, 4H); FDMS 526 (M+1). Anal. (C31H31N3O5) C, H, N.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared as above from 337.8 mg (0.86 mmol) of the pyridyl ketone and 742 mg (1.63 mmol) of the Wittig salt. Flash chromatography with MeOH-AcOH-CH2Cl2 (3:2:95) gave in ~92% yield a mixture of Wittig product (E/Z=~7.7:1) from which 326.5 mg (78%) of (E)-heptenoic acid was isolated cleanly: mp 61-64° C.; 1H NMR (CDCl3) δ8.57 (d, J=1.7 Hz, 1H), 8.47 (d, J=4.1 Hz, 1H), 8.28 (s, 1H), 8.05 (d, J=8.2 Hz, 2H), 7.52 (t, J=5.7 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.25 (m, 5H), 6.94 (d, J=8.2 Hz, 2H), 6.94 (buried, 1H), 6.18 (t, J=7.4 Hz, 1H), 4.15 (t, J=5.0 Hz, 2H), 3.87 (dt, J=5.4, 5.3 Hz, 2H), 2.31 (dd, J=7.1, 6.7 Hz, 2H), 2.19 (ddd, J=7.3, 7.1, 6.9 Hz, 2H), 1.67-1.51 (m, 4H); FDMS 512 (M+1). Anal. (C30H29N3O5) C, H, N.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared as above from 376.4 mg (0.86 mmol) of the (±)-pyridyl ketone and 790.6 mg (1.73 mmol) of the Wittig salt. Preparative HPLC with MeOH-AcOH-CH2Cl2 (4:1:95) gave in ~92% yield a mixture of Wittig product (E/Z=~96:4) from which 320.9 mg (70%) of (±)-(E)-heptenoic acid was isolated cleanly: mp 68-73° C.; 1H NMR (CDCl3) δ8.61 (br s, 1H), 8.49 (br s, 1H), 8.28 (s, 1H), 8.06 (d, J=8.1 Hz, 2H), 7.52 (br s, 1H), 7.46 (br d, J=8.0 Hz, 1H), 7.28 (d, 2H), 7.27 (buried, 1H), 6.21 (t, J=7.4 Hz, 1H), 4.04 (dt, J=13.3, 1.9 Hz, 1H), 3.69 (br s, 4H), 3.50 (m, 5H), 2.33 (dd, J=7.1, 6.7 Hz, 2H), 2.21 (ddd, J=7.2, 7.0, 6.7 Hz, 2H), 1.89-1.26 (m, 10H); FDMS 534 (M+1). Anal. (C30H35N3O6.0.25C2H4O2) C, H, N.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (0° C.) solution of 293.6 mg (0.74 mmol) of the pyridyl ketone and 670.4 mg (1.48 mmol) of (5-carboxypentyl)-triphenylphosphonium bromide in 2.5 mL of THF was added dropwise 2.95 mL (2.95 mmol) of 1.0 M t-BuOK in THF over 10 min period. The dark brown solution was stirred at 0° C. for 1.5 h, and then the reaction was quenched with 20 mL of saturated aqueous NH4Cl. The mixture was extracted with 3×50 mL of CH2Cl2. The combined extract was dried over MgSO4, concentrated and purified by preparative HPLC with MeOH-AcOH-CH2Cl2 (2:1:97) as the eluent to afford 56.1 mg (8.4%) of the less polar (Z)-heptenoic acid and 434.9 mg of the (E)-isomer containing a byproduct from the Wittig salt. In order to purify it, the (E)-isomer was therefore esterified with CH2N2 which was generated by a standard method from MNNG and aqueous NaOH in Et2O. The ester was isolated cleanly by flash chromatography with EtOAc-hexanes-CH2Cl2 (2:1:1) as the eluent. The ester (102.5 mg) was then hydrolyzed with 1 N NaOH in THF-MeOH (1:1). Flash chromatography with EtOAc-MeOH-AcOH-CH2Cl2 (50:1:1:48) yielded 92.5 mg (25%) of the pure (E)-heptenoic acid: mp 56-61° C.; 1H NMR (CDCl3) δ8.58 (s, 1H), 8.47 (d, J=4.1 Hz, 1H), 8.26 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.44 (dt, J=8.0, 1.5 Hz, 1H), 7.35-7.16 (m, 9H), 6.19 (t, J=7.4 Hz, 1H), 3.70 (dt, J=6.9, 6.7 Hz, 2H), 2.94 (t, J=7.2 Hz, 2H), 2.32 (t, J=7.8 Hz, 2H), 2.20 (ddd, J=7.3, 7.2, 7.0 Hz, 2H), 1.68-1.5:(m, 4H); FDMS 496 (M+1). Anal. (C30H29N3O4.0.1C2H4O2) C, H, N.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 101.5 mg (0.13 mmol) of the compound from example 29A and 23.0 mg (0.17 mmol) of trans-2-heptenoic acid are introduced under argon into anhydrous dimethylformamide (2 ml) at 0° C. and then 65.0 mg (0.17 mmol) of HATU and 0.025 ml (0.14 mmol) of ethyldiisopropylamine are added. After 30 min, a further 0.05 ml (0.29 mmol) of ethyldiisopropylamine are added to the reaction mixture. The reaction mixture is stirred overnight with slow warming to RT. The reaction solution is subjected directly to an RP-HPLC using acetonitrile/water as eluent. In the course of this, 63 mg (62% of th.) of a colorless solid are obtained. In the course of this, 63 mg (62% of th.) of a colorless solid are obtained

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.89 g (2.75 mmol) of the compound from example 13A and 458.8 mg (3.58 mmol) of trans-2-heptenoic acid are introduced into dichloromethane (20 ml), cooled to 0° C., then treated with 2.09 g (5.51 mmol) of HATU and 462.7 mg (3.58 mmol) of ethyldiisopropylamine. The solution is stirred at 0° C. for 30 min, then a further 925.3 mg (7.16 mmol) of ethyldiisopropylamine are added, and it is stirred at room temperature for 18 h. The reaction solution is evaporated, and the residue is taken up using ethyl acetate and washed with aq. citric acid, aq. sodium hydrogencarbonate solution and sat. aq. sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. The residue is chromatographed on silica gel using ethyl acetate/cyclohexane 1/2. 1.51 g (56% of th.) of the product are obtained. it is stirred at room temperature for 18 h The reaction solution is evaporated washed with aq. citric acid, aq. sodium hydrogencarbonate solution and sat. aq. sodium chloride solution dried over sodium sulfate filtered concentrated to dryness The residue is chromatographed on silica gel 1.51 g (56% of th.) of the product are obtained

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2.89 g (2.75 mmol) of the compound from example 13A and 458.8 mg (3.58 mmol) of trans-2-heptenoic acid are introduced into dichloromethane (20 ml), cooled to 0° C., then treated with 2.09 g (5.51 mmol) of HATU and 462.7 mg (3.58 mmol) of ethyldiisopropylamine. The solution is stirred at 0° C. for 30 min, then a further 925.3 mg (7.16 mmol) of ethyldiisopropylamine are added, and it is stirred at room temperature for 18 h. The reaction solution is evaporated, and the residue is taken up using ethyl acetate and washed with aq. citric acid, aq. sodium hydrogencarbonate solution and sat. aq. sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. The residue is chromatographed on silica gel using ethyl acetate/cyclohexane 1/2. 1.51 g (56% of th.) of the product are obtained. it is stirred at room temperature for 18 h The reaction solution is evaporated washed with aq. citric acid, aq. sodium hydrogencarbonate solution and sat. aq. sodium chloride solution dried over sodium sulfate filtered concentrated to dryness The residue is chromatographed on silica gel 1.51 g (56% of th.) of the product are obtained

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 74.79 ml (312 mmol) of 1,2-(di-tert-butyl)trimethylamine were added to a stirred mixture of 5 g (39 mmol) of (E)-2-heptenoic acid in 100 ml of toluene at 80° C. The mixture was stirred under reflux for 30 minutes and then cooled to room temperature. The mixture was washed in sequence with water and saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulphate and filtered. The solvent was removed by evaporation. There were obtained 7.5 g of tert-butyl (E)-2-heptenoate as a yellow oil; MS: m/e 185.0 [M+H]. under reflux for 30 minutes The mixture was washed in sequence with water and saturated sodium bicarbonate solution dried over anhydrous magnesium sulphate filtered The solvent was removed by evaporation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 74.79 ml (312 mmol) of 1,2-(di-tert-butyl)trimethylamine were added to a stirred mixture of 5 g (39 mmol) of (E)-2-heptenoic acid in 100 ml of toluene at 80° C. The mixture was stirred under reflux for 30 minutes and then cooled to room temperature. The mixture was washed in sequence with water and saturated sodium bicarbonate solution, then dried over anhydrous magnesium sulphate and filtered. The solvent was removed by evaporation. There were obtained 7.5 g of tert-butyl (E)-2-heptenoate as a yellow oil; MS: m/e 185.0 [M+H]. under reflux for 30 minutes The mixture was washed in sequence with water and saturated sodium bicarbonate solution dried over anhydrous magnesium sulphate filtered The solvent was removed by evaporation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared as above from 165.4 mg (0.44 mmol) of the pyridyl ketone and 395.6 mg (0.87 mmol) of the Wittig salt. Preparative HPLC with MeOH-AcOH-CH2Cl2 (2:1:97) furnished 94.8 mg (46%) of the pure (E)-heptenoic acid: mp 67-72° C.; 1H NMR (CDCl3) δ8.60 (s, 1H), 8.48 (br s, 1H), 8.25 (s, 1H), 8.05 (d, J=8.2 Hz, 2H), 7.62 (distorted t, J=~5.3 Hz, 1H), 7.43 (br d, J=7.8 Hz, 1H), 7.28 (buried, 1H), 7.26 (d, 2H), 6.22 (t, J=7.4 Hz, 1H), 3.50 (m, 6H), 2.30 (ddd, J=7.1, 7.1, 6.9 Hz, 2H), 2.20 (ddd, J=7.6, 7.2, 6.9 Hz, 2H), 1.90 (tt, J=6.1, 6.1 Hz, 2H), 1.64-1.54 (m, 4H), 1.28 (t, J=7.0 Hz, 3H); FDMS 478 (M+1). Anal. (C27H31N3O5.0.6CH4O.0.8H2O) C, H, N.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared as above from 375.3 mg (0.88 mmol) of the pyridyl ketone and 796.8 mg (1.76 mmol) of the Wittig salt. Preparative HPLC with MeOH-AcOH-CH2Cl2 (4:1:95) yielded 266.2 mg (58%) of the pure (E)-heptenoic acid as a white fluffy sold: mp 48-55° C.; 1H NMR (CDCl3) δ8.60 (br s, 1H), 8.48 (br s, 1H), 8.26 (s, 1H), 8.06 (d, J=8.2 Hz, 2H), 7.48 (br s, 1H), 7.46 (br s, 1H), 7.38-7.25 (m, 6H), 7.27 (d, J=8.2 Hz, 2H), 6.20 (t, J=7.4 Hz, 1H), 4.57 (s, 2H), 3.67 (s, 4H), 2.32 (dd, J=7.1, 6.8 Hz, 2H), 2.20 (ddd, J=7.3, 7.2, 6.8 Hz, 2H), 1.68-1.52 (m, 4H); FDMS 526 (M+1). Anal. (C31H31N3O5) C, H, N.